Antidepressant arylpiperazine derivatives of heterocycle-fused benzodioxans

• US 20060276481A1
• Filed: 08/16/2006
• Published: 12/07/2006
• Est. Priority Date: 09/12/2002
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Venkatesan, Aranapakam Madumbai, Zhou, Dahui, Failli, Amedeo A., Stack, Gary Paul, Croce, Susan Christman, Evrard, Deborah Ann
• Application Number:
  US11/505,663
• Publication Number:
  US 20060276481A1
• Time in Patent Office: Days
• US Class Current: 514/253.30
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/32 Alcohol-abuse
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/14 Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: Y02P 20/582 Recycling of unreacted starting or intermediate materials

Abstract

Compounds of the formula I: are useful for the treatment of depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa and bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction and related illnesses.

Claims

1. A method of treating a subject suffering from a condition selected from depression, anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder, attention deficit disorder, obsessive-compulsive disorder, social anxiety disorder, generalized anxiety disorder, obesity, eating disorders, vasomotor flushing, cocaine and alcohol addiction, and sexual dysfunction, comprising the step of:

providing to said subject a therapeutically effective amount of (2S)-2-{[4-(dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline, or a pharmaceutically acceptable salt thereof.

2. The method according to claim 1, wherein said condition is depression.

3. The method according to claim 1, wherein said condition is selected from the group consisting of obsessive-compulsive disorder, panic attacks, generalized anxiety disorder, and social anxiety disorder.

4. A method of treating a subject suffering from cocaine addiction, comprising the step of:

providing to said subject a therapeutically effective amount of a compound of formula I

wherein

R¹ is hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;

the group X—

Y is —

N═

C(R²)—

C(R³)═

N—

, —

N═

C(R²)—

C(R⁴)═

CH—

, —

N═

C(R²)—

N═

CH—

, —

N═

C(R²)—

O—

, or —

NH—

C(R⁵)═

CH—

;

R² and R³ are, independently, hydrogen, halo, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms;

R⁴ is hydrogen or alkyl of 1 to 6 carbon atoms;

R⁵ is hydrogen, halo, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms;

Ar is phenyl, naphthyl, indolyl, indazolyl, thienyl, pyridinyl, pyrimidinyl, quinolinyl, benzofuranyl, benzothienyl, benzoisothiazolyl, or benzisoxazolyl, each optionally substituted with one to three substituents independently selected from hydroxy, halo, cyano, carboxamido, carboalkoxy of 2 to 6 carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms; and

,

n is 1 or 2;

or a pharmaceutically acceptable salt thereof.

5. The method according to claim 4, wherein R¹ is hydrogen, halo, cyano, trifluoromethyl, alkyl of 1 to 6 carbon atoms or alkoxy of 1 to 6 carbon atoms.

6. The method according to claim 4, wherein R¹ is hydrogen, halo or alkoxy of 1 to 6 carbon atoms.

7. The method according to claim 4, wherein R¹ is hydrogen.

8. The method according to claim 4, wherein Ar is phenyl, quinolinyl, benzofuranyl, benzothienyl, or indolyl, each optionally substituted.

9. The method according to claim 4, wherein X—

Y is —

N═

C(R²)—

C(R⁴)═

CH— and

R⁴ is hydrogen or alkyl of 1 to 3 carbon atoms.

10. The method according to claim 4, wherein R² and R³ when present are independently selected from the group consisting of hydrogen, amino, and alkyl of 1 to 6 carbon atoms.

11. The method according to claim 4, wherein R⁵ is hydrogen, trifluoromethyl, pentafluoroethyl or alkyl of 1 to 6 carbon atoms.

12. The method according to claim 4, wherein R⁵ is hydrogen, trifluoromethyl or alkyl of 1 to 3 carbon atoms.

13. The method according to claim 4, wherein said compound is selected from the group consisting:

(2S)-2-{[4-(3-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(4-chlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(3,4-dichlorophenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxine[2,3-f]quinoline;

(2S)-2-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(3-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(4-methoxyphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-[4-(3-trifluoromethyl-phenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-[4-(3-fluorophenyl)piperazin-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(2,3-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(3,4-dimethylphenyl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-[(4-quinolin-2-ylpiperazin-1-yl)methyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

((2S)-8-methyl-2-{4-(6-nitroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-{4-(6-chloroquinolin-2-yl)piperazin-1-yl]methyl)-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

2-(4-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}piperazin-1-yl}quinoline-6-carbonitrile;

(2S)-2-{[4-(1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(5-fluoro-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

((2S)-2-{[4-(7-methoxy-1-benzofuran-3-yl)-1-piperazinyl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-{[(2S)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

2-((3R)-3-methyl-4-{[(2S))-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}piperazin-1-yl]quinoline-6-carbonitrile;

(2S)-8-methyl-2-{[(2R)-2-methyl-4-quinolin-2-ylpiperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-8-methyl-2-{[4-(2-naphthyl)piperazin-1-yl]methyl}-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-[4-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-yl)-piperazin-1-yl]-quinoline-6-carboxylic acid amide;

(2S)-2-[4-(2,3-Dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;

(2S)-2-[4-(8-Ethyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinolin-2-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;

(2S)-2-[4-(2-Methyl-7,8-dihydro-1,6,9-trioxa-3-aza-cyclopenta[a]naphthalen-8-ylmethyl)-piperazin-1-yl]-quinoline-6-carbonitrile;

(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(6-Bromoquinolin-2-yl)piperazin-1-yl]methyl}-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(6-methoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(6-Trifluoromethoxyquinolin-2-yl)piperazin-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

2-[4-(6-Fluoro-quinolin-2-yl)-piperazin-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(6-methoxyquinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

2-(4-{[(2S)-8-Methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}-1,4-diazepan-1-yl)quinoline-6-carbonitrile;

(2S)-2-{[4-(6-Trifluoromethoxy-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

2-[4-(6-Fluoro-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-8-methyl-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline;

(2S)-2-{[4-(6-Bromo-quinolin-2-yl)-1,4-diazepan-1-yl]methyl]-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline;

8-Methyl-2-(4-quinolin-2-yl-[1,4]diazepan-1-ylmethyl)-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline; and

,

8-Methyl-2-[4-(4-methyl-quinolin-2-yl)-[1,4]diazepan-1-ylmethyl]-2,3-dihydro[1,4]dioxino[2,3-f]quinoline, and

pharmaceutically acceptable salts thereof.